Stress Starts Up The Machinery of Major Depression

New revelations about the nuts and bolts of major depression focus on the role of stress

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Ella Cohen

Updated April 28, 2014 12:54 p.m. ET

It's hard not to be pulled by the sheer terror of some exotic diseases. Headlines are commanded by the tragedies of the likes of Ebola virus, mad-cow disease or progeria. But when it comes to everyday medical misery, nothing quite beats major depression. It sucks the very air out of life, cripples millions of people (about 15% of us) and, within a decade, is likely to be the second leading cause of global medical disability.

Many factors increase the risk of major depression, including variants of a number of genes, childhood trauma and endocrine and immunological abnormalities. A frequent trigger is stress. Recent research shows how this might occur.

The stress angle concerns "anhedonia," psychiatric jargon for "the inability to feel pleasure." Anhedonia is at the core of the classic definition of major depression as "malignant sadness."

The abilities to anticipate, pursue and feel pleasure revolve around a neurotransmitter called dopamine in a brain region called the nucleus accumbens. Publishing in the journals Nature and Nature Neuroscience, Julia Lemos, Matthew Wanat and Paul Phillips of the University of Washington and colleagues explored the effects of stress on dopamine in mice. Rather than taking the easy path of studying the rewarding properties of a slam-dunk like sex or yummy food, the authors looked at a subtler pleasure.

ENLARGE

New research reveals some of the nuts-and-bolts biology of how depression works.
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Put a novel object—say, a ball—in a mouse's cage. When the mouse encounters the ball and explores it, the arousing mystery, puzzle and challenge cause the release of a molecule in the nucleus accumbens called CRF, which boosts dopamine release. If the unexpected novel object was a cat, that mouse's brain would work very differently. But getting the optimal amount of challenge, what we'd call "stimulation," feels good.

CRF mediates this reaction: Block the molecule's actions with a drug and there is no longer the dopamine surge or the exploration. Or, in another experimental approach, if you spritz CRF into the nucleus accumbens whenever a mouse wanders into one corner of the cage, the mouse returns to that spot repeatedly; in other words, CRF has "reinforcing properties."

But exposing a mouse to major, sustained stress for a few days changes everything. CRF no longer enhances dopamine release, and the mouse avoids the novel object. Moreover, the CRF is now aversive: Spritz it into the nucleus accumbens and the mouse now avoids the place in the cage where that happened. The authors showed that this is due to the effects of stress hormones called glucocorticoids. A switch has been flipped; stimuli that would normally evoke motivated exploration and a sense of reward now evoke the opposite. Remarkably, those few days of stress caused that anhedonic state to last in those mice for at least three months.

Like all good research, more questions are raised: How do glucocorticoids cause these changes? Do mice ever recover? Are some individuals resistant to these effects? And does it work this way in humans?

But meanwhile, these findings have an important implication. Life throws lousy things at us; at times, we all get depressed, with a small letter "d." And most people—as the clichés say—get back in the saddle, prove that when the going gets tough, the tough get going. What then to make of people who are incapacitated by major depression in the clinical sense? Unfortunately, for many, an easy explanation is that the illness is a problem of insufficient gumption: "Come on, pull yourself together." There is a vague moral taint.

Thus, it isn't just a medical but also a social good when scientists reveal more of the nuts-and-bolts biology of how depression works, because the studies underline in the process that the illness is a real biological disorder. It is as real as diabetes, and we don't sit down a diabetic and say, "Come on, stop indulging yourself, you've got to overcome this fixation of yours about insulin."

Corrections & Amplifications An earlier version of this article omitted Julia Lemos as an author of research on stress and dopamine.

From my own family history, I'm convinced that there is a strong genetic element in severe depression but again from my family, severe stress can trigger life-long, life-threatening depression in a particular individual. This research illuminating the physiological link between stress and depression is very welcome.

Some of the most promising depression research involves low-dose infusions of the anesthetic ketamine. Dozens of studies have been underway for nearly 15 years at Yale, the National Institutes of Health, Mt. Sinai, the Mayo Clinic, and elsewhere. About 70% of treatment-resistant patients experience rapid relief of symptoms, though its long-term efficacy has not yet been studied. A growing number of US doctors are now using ketamine clinically to treat severe depression cases. An advocacy group, the Ketamine Advocacy Network, has sprung up to encourage clinical use. Their website (www.ketaminenetwork.org) has an FAQ about the treatment, a directory of doctors who offer it, and discussion forums for ketamine patients.

Interesting. Since Americans are so stressed out because of Obstructionism we can expect that Republicans will continue to lead the parade of "A Depressed America" . Nothing has been done for the Average American in 5 years---except Obamacare --which many want to destroy anyway.

I once read of a study that showed that the act of smiling can make a person happy - kind of like the cart pulling the horse. I don't mean to suggest in any way that depressed people choose depression and happy people choose happiness. I have had struggles with depression in the past and it is a pit of vipers that can be extremely difficult to get out of. In my case like many stress was a major factor in causing my depression. The results of this study with mice is not in the least bit surprising to me.

When I read articles about psychology and mental health that result from actual scientific research, it makes me very angry with physicians like Freud, who told us all in "Mourning and Melancholia" that depression was "anger turned inward." The Hippocratic oath says that physicians should not do harm to their patients. By creating theories that they presented as "truth," generations of physicians and therapists have ruined lives instead of helping. Hopefully, a new generation has emerged in the medical community that is willing to say, "We don't know" until the real cause of any illness is found.

I began to suffer severe depression with the convergence of financial loss during the recession on top of a brother who was dying at an early age. I was then involved in three law suits followed by the suicide of my best friend. My brother died 4 months later. That was almost two years ago and I'm finally pulling out.

Don't let anyone kid you about whether depression is real. During this time I might get some bad news or hear someone say something negative and the rush of depression came over me like a narcotic coursing thru my veins. It felt very much like a drug in my system. I could not bear the though of hurting myself or my family, but I wanted to die.

Thank goodness this is almost past me, but it's not over yet. For others out there that feel the same way, don't lose hope and don't be afraid to tell someone how you feel.

I always found it interesting that most reports on depression cite the percentage of the population that suffers from depression between 15-20%. Maybe I'm wrong, but I feel like it is much higher than that. Some people are better at living with it or hiding it, but I would say as a hard working society we are generally very stressed out.

So depression is an inflammatory disease, but where does the inflammation come from?:"We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is 'what is the source of this chronic low-grade inflammation?'"

For two months I have been taking the UMAC Core marine phytoplankton extract capsules, at one capsule per day at about 11 AM, and I would enthusiastically recommend plankton to people under stress. Plankton has tens or hundreds of nutrients which feed the brain. I can certainly feel and literally "hear" the increased activity in my brain when I take the UMAC plankton extract.For example, the omega-3's in plankton can pass through the blood-brain barrier because they are still hooked on to phospholipids, making them super absorbable unlike omega-3's in fish oil which are hooked on to triglycerides.

I wanted to also try a non-extract plankton, so I ordered the Sunn Herbal plankton capsules from Amazon, although I haven't tried them yet. They are 500 mg of plankton per capsule whereas the UMAC extract is 250 mg of plankton equivalent per capsule.I think plankton would be the perfect supplement for our depressed, demoralized troops in the military to try, effectively bypassing or eliminating the need for dangerous and harmful psychotropics that soldiers and veterans are put on.Also, the elderly and those in nursing homes need to try plankton. All it would take is probably just one capsule per day, as a website states that plankton has 400 times more energy than any other living material. Whales eat plankton and whales live up to 200 years.Students and anyone needing their brain to work well should try plankton.Basically, I think everyone needs to try plankton.

My husband and I have this going on. We're doing all right but man! Now I see why we avoid things we used to enjoy. I'm working on better nutrition and some outdoor exercises but it's going to take a long and steady climb and even a commitment to keep going until we start to shine like we used to.

Agree, most doctors don't know squat about treating mental illnesses. Medical science knows very little about mental illnesses. Good to see scientists learning more about this bit by bit.The really good ones honestly admin that they don't know. The really bad ones spend an average 3 minutes with a patient and hand them a prescription and some sample tablets that a pharma salesperson gave them to push to patients.

Mr Bates, my deepest condolences. You actually have an obvious, completely justified reason for your depression. The problem in today's world is the people who are depressed who have no reason to be, which to me is a result of people's lives being too easy. Your depression is a natural reaction to the events of your life, unlike a lot of today's narcissists, whose lives are nothing but peaches and cream and have to conjure up something to "suffer".

@Leslie: you're right, that IS what I mean. I realize that in today's society, that must sound harsh and judgemental. I sincerely hope you don't go through a stretch in your life like Mr. Bates has recently experienced, but if you ever do, I assure you that the things that cause your current depression symptoms will seem like ridiculous things to be depressed about. Speaking from personal experience, many of the things that people find that make them depressed(not necessarily you) don't even show up on my radar of "hardships". I've had enough bad things I've gone through to not get depressed over nothing. I'm not trying to assume things about your life experiences, I'm just saying that if someone's family is killed in a car accident, a few years later, the same person not getting the big promotion at work, won't send them into a death cycle of depression drug cocktails.

A mouse is the best animal model they had available at the time. Perhaps they could use chimps for this, but that is expensive and may be considered inhumane by today's standards. Whether the same things happen in humans would require a lot more money and time. You use the cheapest system to test your hypothesis and go onto more relevant species.

It will be a great day when science figures out customized treatment for depression. The current batch of antidepressants are crude cudgels that only work on a third of patients. There are promising treatments out there involving psychedelics and other drugs such as ketamine and MDMA but burdensome regulatory processes will take many years before they reach the market. This is very unfortunate as some of these treatments should be fast tracked. Off label ketamine infusions are available in some states but the treatment is not covered by insurance. Ibogaine, illegal in the US, is available in Mexico, Costa Rica and Canada.

"...I'm just saying that if someone's family is killed in a car accident, a few years later, the same person not getting the big promotion at work, won't send them into a death cycle of depression drug cocktails."

This isn't what I'm talking about, nor is this article. My expectation would be that someone who suffered some major emotional trauma without becoming clinically depressed would also not become depressed by some lesser life stress later. Though I wouldn't assume it to be necessarily the case, since the brain is a complicated organ. Who knows, it could be a 'straw that broke the camel's back' situation to not get the promotion in your hypothetical.

My main problem is with this statement of yours,

"Speaking from personal experience, many of the things that people find that make them depressed(not necessarily you) don't even show up on my radar of "hardships"."

Again, you are making a personal value judgement as to whether people suffering a medical condition have a justified reason to really be considered 'sick'. As an analogy, consider this:

Two people, close to the same age and similarly healthy in their diet and lifestyles, each get an infection, say the same strain of the flu. Bob stays home a day or two, drinks plenty of fluids and takes some vitamin C, along with some OTC medicine for his symptoms. Then he gets better and goes back to work. Jim tries the same routine, but quickly gets worse and ends up in the hospital, almost becoming a statistic of how many people in the US die from influenza every year.

Is Jim somehow morally responsible for his own situation because most people are able to shake off the flu without being hospitalized? Should he have been able to suck it up and deal with it like everyone else?

This is the whole point of the article: Depression isn't just what people 'feel' and think, it isn't well understood (from a biological point of view, especially) why some people get depressed from stresses that others shake off, and it isn't a matter of willpower alone to pull out of it. Telling people that they shouldn't be depressed from their relatively mild stresses actually feeds into negative patterns of thinking they already have. This stigma is hugely counterproductive to actually treating depression better.

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